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- Nye, Taylor M., et al.
(författare)
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Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : PNAS. - 0027-8424 .- 1091-6490. ; 119:43
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Tidskriftsartikel (refereegranskat)abstract
- The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.
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- Tükenmez, Hasan, 1987-, et al.
(författare)
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Complete Genome Sequence of the Uropathogenic Methicillin-Resistant Staphylococcus aureus Strain MRSA-1369
- 2022
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Ingår i: Microbiology Resource Announcements. - : American Society for Microbiology. - 2576-098X. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- MRSA-1369 is a uropathogenic methicillin-resistant Staphylococcus aureus (MRSA) strain. Here, we present the complete genome sequence of MRSA-1369, which consists of one chromosome (2.87 Mb) and two plasmids (16.68 kb and 3.13 kb). This will serve as a reference genome for future Staphylococcus aureus pathogenesis and multiomic studies.
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- Winblad, B, et al.
(författare)
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Safety and efficacy of galantamine in subjects with mild cognitive impairment.
- 2008
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 1526-632X .- 0028-3878. ; 70:22, s. 2024-35
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the safety of galantamine in subjects with mild cognitive impairment (MCI), the ability of galantamine to benefit cognition and global functioning in subjects with MCI, and the ability of galantamine to delay conversion to dementia. METHODS: In two studies, 2,048 subjects, 990 in Study 1 and 1,058 in Study 2, with a Clinical Dementia Rating (CDR) = 0.5, CDR memory score > or =0.5, without dementia were randomized to double-blind galantamine (16-24 mg/day) or placebo for 24 months. Primary efficacy endpoint at month 24 was number (%) of subjects who converted from MCI to dementia (CDR > or = 1.0). RESULTS: There were no differences between galantamine and placebo in 24-month conversion rates (Study 1: 22.9% [galantamine] vs 22.6% [placebo], p = 0.146; Study 2: 25.4% [galantamine] vs 31.2% [placebo], p = 0.619). Mean CDR-sum of boxes declined less with galantamine than placebo at 12 and 24 months in Study 1 (p = 0.024 [12 months] and p = 0.028 [24 months]), but not in Study 2 (p = 0.662 [12 months] and p = 0.056 [24 months]). Digit Symbol Substitution Test scores improved with galantamine in Study 1 at 12 months and in Study 2 at 24 months (Study 1: p = 0.009 [month 12] and p = 0.079 [Month 24]; Study 2: p = 0.154 [month 12] and p = 0.020 [month 24]). The most frequently reported adverse event was nausea (galantamine, 29%; placebo, 10%). Serious AEs occurred in 19% of each group. Mortality of the cohort after retrospectively determining the status of subjects (98.3%) at 24 months was 1.4% (galantamine) and 0.3% (placebo); RR (95% CI), 1.70 (1.00, 2.90). CONCLUSIONS: Galantamine failed to significantly influence conversion to dementia. Galantamine was generally well tolerated. Whereas recorded mortality was greater in the galantamine group than in the placebo group in the original per-protocol assessment, a post hoc analysis of the cohort was consistent with no increased risk.
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